6 min readBengaluruJun 6, 2022 08:17 AM IST
First published on: Jun 3, 2022 at 02:26 PM IST
Most mammals, including humans, are diploid. That is, nuclear DNA (nrDNA) exists as pairs of chromosomes (humans have 23 pairs of chromosomes, while mice have 20). This pair of chromosomes are homologous, in that the sequence of genes on both the chromosomes is the same. However, a gene that sits on a particular address (‘locus’) could have different ‘alleles’ on the homologous chromosomes. For the sake of understanding, if we were to assume that height is determined by a particular gene that sits on, let’s say, the 6th chromosome, one of the chromosomes could be carrying a genetic sequence for short height – rather, ‘allele’ for shortness – and the other one could be carrying the gene for tallness. (In reality, no one gene is responsible for height and it is a trait determined by a combination of genes, not least environment and nutrition). In this make-believe example above, if both the chromosomes in the pair were to carry the allele for shortness, then we’d say that the individual, or the sequence, is homozygous for shortness at that locus, or heterozygous if both chromosomes were to carry different alleles. The same logic applies even when we consider species where the genetic code exists in triplets and not pairs, a condition known as triploid.
This determines the genotype of an individual for that particular trait/gene/locus. For example, for a flower species that could have white and yellow flowers, a particular flower’s genotype could be YY (alleles for a yellow flower on both chromosomes) or WY or YW (one allele on either) or WW (white allele on both). If W were the recessive allele, and Y the dominant, a heterozygote flower will have a yellow phenotype.
A deleterious allele puts the individual at a disadvantage in some way. A deleterious allele can very much be the dominant one. But, in that case, it is going to reduce the individual’s fitness and the genotype is going to have less of a chance of being passed on to the next generation.
However, matters get complicated when the same genotype results in different phenotypes – a phenomenon called allele-specific expression (ASE). A study published this week by a team of researchers from Canada sheds light on that. They find that regions of the genome that are likely to undergo recombination are also more likely to flush out a set of deleterious alleles.
Recombination is a phenomenon whereby chromosomes in a pair are broken up, their codes recombined to produce a new sequence of alleles. It is characteristic of meiosis, a kind of cell division that takes place when gamete cells (the sperms or the ova) are being formed. The resultant sequence in sperms/ova is monoploid meaning it does not exist as a pair. The pair is only formed when the sperm and ovum fuse. A set of alleles/traits that are passed from one generation to another is known as a ‘haplotype’.
There are regions of the genome that display a greater affinity for recombination (recombination hotspots) and then there are regions that display a lesser affinity for the same (coldspots). The latter naturally allows deleterious mutations to accumulate and reach what we call ‘fixation.’ Harwood et al (2022) classify recombination regions as low (ie coldspot, CS), normal and high recombination (HRR). The study genotyped nearly 1596 individuals and measured their allele expression. These 1596 individuals consisted of 844 individuals from Quebec, Canada, as part of the CARTaGENE project and 752 from the Genotype Tissue Expression project. It was found that ‘enrichment of ASE in HRR/normal regions was observed in all the tissues examined.’
Capitalising on the Genotype Tissue Expression Project (GTEx), a previous study in 2018 had established that, in a general population, purifying selection depletes those haplotypes where deleterious mutations have accumulated and will likely have an ‘increased pathogenic penetrance.’ They had also found that in cancer patients, the penetrance of these deleterious haplotype configurations is enriched. Extending this finding, Harwood et al (2022) observed that in regions of high or normal recombination, potentially disease-causing alleles are underexpressed, and overexpressed in recombination coldspots.
It is important to note the historical context of Quebec, Canada as well. The population was settled by French colonisers 400 years back, along with smaller colonies such as in the Saguenay-Lac-Saint-Jean region. It is also well known that when the population size is small, there are greater chances of non-random associations among alleles from different loci, due to a reduced gene pool. Natural selection has little genetic diversity left to work with in that case – and it is rendered quite inefficient. Therefore, the Saguenay region shows a high level of relatedness, compared to African or European populations that have more efficient natural selection processes acting on them. ‘The signature of African individuals having increased odds of ASE in HRR/Normal compared to CS was also demonstrated in GTEx muscle, brain, ovarian, lung, and liver tissue,’ the study argues.
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Environmental histories play a key role as well, the study finds. While examining genes that had yielded expression data across regions and environments. They observed that individuals with ancestry in Saguenay but currently residing in different regions such as Montreal, Quebec City and Saguenay, had ‘differential allele-specific expression.’
The study is an important step in understanding a longstanding question in evolutionary biology: how past demographic changes, population sizes and genetic drift interact with recombination and influence gene expression. Highlighting its implications in predicting disease risks in populations, the study says that ‘gene expression is a key intermediate step in translating genotypes into phenotypes, and thus understanding how gene expression is regulated and evolves is critical for deconvoluting the relationship between phenotypic variation and disease penetrance across human populations.’
The author is a research fellow at the Indian Institute of Science (IISc), Bengaluru, and a freelance science communicator. He tweets at @critvik.
Recombination, put simply, is a phenomenon whereby chromosomes in a pair are broken up, their codes recombined to produce a new sequence of alleles. (Image Source: Pixabay) 
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